KR910007887B1 - Process for the preparation of 1,4 - diazabicyclo (3,2,2) nonane - Google Patents

Abstract

Processes and intermediates for preparing 1,4-diazabicyclo[3.2.2.]nonane including a process for the preparation of a compound of the formula <CHEM> wherein R<1> is C1-C4 alkyl or C1-C4 alkyl substituted with 1 to 6 halo groups; and R<2> is as defined herein, by reacting a compound of the formula <CHEM> wherein R<1> and R<3> are independently selected from C1-C4 alkyl and C1-C4 alkyl substituted with 1 to 6 halo groups with an alkyl stannane or a trialkyl aluminum.

Description

1,4-diazabicyclo [3.2.2] nonane manufacturing method

The present invention relates to a process for the preparation of 1,4-diazabicyclo [3.2.2] nonane and to intermediate compounds.

The compounds described in Zhurnal Obshchei Khimii, 33 (7), 2167-2172 (1963) include the antimicrobial compound 7- (1,4-diazabicyclo [3.2. 2] non-4-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methane sulfonate. Other quinolinecarboxylic acids that may react similarly to 1,4-diazabicyclo [3.2.2] nonane to produce antimicrobial compounds are described in US Pat. No. 4,571,396.

The present invention reacts naphtha chloride naph with the following general formula (II) compound reacted with alkyl tin hydride or trialkyl aluminum and optionally substituted with the following general formula (III) compound where R ² is hydrogen: Toyl, brominated naphthoyl, naphthoyl triflate, benzoyl chloride, benzoyl bromide, benzoyl triflate, benzyl chloride, benzyl bromide and benzyl triflate where substituted naphthoyl, substituted benzyl and substituted benzoyl phase substituents are Reacting with a reactant selected from the group consisting of: to form a compound of formula (III), wherein R ² is defined below but excludes hydrogen. It relates to a process for the preparation of a compound.

Wherein R, R ¹ and R ³ are independent selected from a C ₁ -C ₄ alkyl, and 1-6 halo groups C ₁ -C ₄ alkyl substituted by one another.

Wherein, R ¹ is C ₁ -C ₄ alkyl or haloalkyl group of 1 to 6 substituted by C ₁ -C ₄ alkyl; R ² is hydrogen, naphthoyl, substituted naphthoyl, benzyl, substituted benzyl, benzoyl or substituted benzoyl, wherein each of the substituted naphthoyl, substituted benzyl and substituted benzoyl is halo, C ₁ -C ₄ alkoxy And 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ alkyl.

As used herein, and unless indicated otherwise, halo includes fluoro, chloro, bromo and iodo. In a preferred embodiment of the present invention, R ¹ and R ³ are the same. In another preferred aspect of the invention, R ² is benzoyl. More preferably, R ¹ and R ³ are the same and R ² is benzoyl. Preferred reactants for the preparation of the general formula (III) compounds wherein R ² is as defined above but excludes hydrogen are the aforementioned chlorides. Most preferred reactant is benzoyl chloride.

The present invention also relates to a process for preparing the following compound of formula (V), comprising reducing the compound of formula (IV) below.

Wherein R ¹ is as defined above and R ² is naphthoyl, substituted naphthoyl, benzyl, substituted benzyl, benzoyl or substituted benzoyl, wherein said substituted naphthoyl, substituted benzyl and substituted Each benzoyl was substituted with one to three substituents selected from the group consisting of halo, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyl.

As a result of the above-described reduction reaction, the benzoyl group and the substituted benzoyl group may be reduced to benzyl group and substituted benzyl group, respectively, and the naphthoyl group and the substituted naphthoyl group are respectively methylnaphthyl group and substituted methylnaphth. It should be noted that it may be reduced to a til group.

The present invention also reacts a compound of formula (V) as defined above with a reactant (e.g. thionyl chloride or thionyl bromide) capable of replacing a hydroxyl group with a leaving group (e.g. chloro or bromo), and After the ring-closure reaction using to and optionally substituted benzyl, optionally substituted methyl naphthyl or optionally substituted benzoyl group to a method of producing a compound of formula (V) comprising hydrogen.

The invention also relates to compounds of the general formula

Wherein Z is C = 0 or CH ₂ and R ² is hydrogen, naphthoyl, substituted naphthoyl, benzyl, substituted benzyl, benzoyl or substituted benzoyl, wherein said substituted naphthoyl, substituted benzyl And each substituted benzoyl is substituted with one to three substituents selected from the group consisting of halo, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyl)

Q is hydrogen and W is —CH ₂ CH ₂ OH, —CH ₂ CH ₂ X or —CH ₂ COOR ¹ , wherein R ¹ is C ₁ -substituted with C ₁ -C ₄ alkyl or 1 to 6 halo groups C ₄ alkyl), X is a leaving group (ie chloro or bromo) or OH or W and Q form an alkylene crosslink of the general formula -CH ₂ CH _2- , provided that W is -CH _{When 2} COOR ¹ Z is C = 0 and when W is —CH ₂ CH ₂ OH or —CH ₂ CH ₂ X or when W and Q form the alkylene crosslink, Z is CH ₂ . Preferred leaving groups are chloro and bromo, and the most preferred leaving group is chloro.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo. Generally fluoro, chloro and bromo are preferred.

The following scheme illustrates the method of the present invention.

Scheme 1

In reaction 1 of Scheme 1, formula (Ⅰ) compound (is selected from wherein R ¹ and R ³ are independently of C ₁ -C ₄ alkyl, and 1-6 halo groups C ₁ -C ₄ alkyl substituted with one another) Was reacted with H ₂ NCH ₂ CH ₂ NH ₂ to prepare the compound of formula (II). It is preferred that R ¹ and R ³ are identical so that no two products are formed in step 2. The solvent should be an inert solvent. Suitable solvents include 1, 2-ethylenediamine, tetrahydrofuran, diethylether, dioxane, dimethoxyethane, benzene, toluene and dimethylformamide. The reaction temperature is not critical but generally ranges from about 10 ° C. to about 45 ° C., with 25 ° C. being the optimum temperature. Formula (I) compounds, wherein R ¹ and R ³ are both ethyl, can be purchased from Aldrich Chemical Company. Other compounds of formula (I) can be prepared as follows:

(a) Method of Lochte from readily available 1, 3-dimethylacetone dicarboxylate [J. Amer. Chem. Soc. 68. 721 (1946)] by the catalytic reduction to alcohol and the removal of the corresponding mesylate with a base.

(여기서 Ph는 페닐이다.)(b) prepared by reaction with dicyclohexyl carbodiimide and dimethylaminopyridine from commercially available glutamic acid and phenol

(Where Ph is phenyl)

(c) prepared by reaction with dicyclohexyl carbodiimide and dimethylaminopyridine from commercially available glutamic acid and fluoro ethanol

(d) prepared as described above from glutamic acid and trifluoroethanol

(e) prepared as described above from glutamic acid and chloroethanol

(f) prepared as described above from glutaconic acid and trichloroethanol

In reaction 2 of Scheme 1, the general formula (II) compound is prepared in an inert solvent, in an alkyl tin hydride (e.g. tri-n-butyltin triflate, mesylate, tosylate or halide), or trialkylaluminum (e.g. Trimethylaluminum), or triethylaluminum or triisobutylaluminum. Of the alkyl tin hydrides described above, tri-n-butyltin triflate is the most reactive. This compound was prepared by Koray's method (described in Tetrahedron Letters, 2419 (1984)). Suitable solvents include tetrahydrofuran, dimethoxyethane and dioxin. The reaction temperature is not critical but generally ranges from about 55 ° to about 100 ° C., with 67 ° C. being the optimum temperature. The tin hydride each of the alkyl groups will preferably have about 1 to about 10 carbon atoms, more preferably about 1 to about 4 carbon atoms. The alkyl group of trialkylaluminum will preferably have from about 1 to about 10 carbon atoms, with trimethylaluminum being preferred. This material can be purchased from Aldrich Chemical Co. as a solution in toluene or as a pure reagent. The product (III) of reaction 2 is generally sent directly to reaction 3 without isolation.

In reaction 3 of Scheme 1, the compound of formula III is naphthoyl chloride, naphthoyl chloride, optionally substituted in an inert solvent in the presence of an organic base (e.g., triethylamine or dimethylaminopyridine) or a mixture of the aforementioned bases. And reacting with a reactant selected from the group consisting of naphthoyl triflate, benzoyl chloride, benzoyl bromide, benzoyl triflate, benzyl chloride, benzyl bromide and benzyl triflate, wherein the substituted naphthoyl, substituted benzyl and substituted benzoyl phases Substituents are as defined above. The reactant is preferably used in excess. Suitable solvents include tetra hydrofuran, dimethoxyethane, dioxane and methylene chloride. The reaction temperature is not critical but will generally range from about −10 ° C. to about 25 ° C., preferably about 0 ° C. Particular nitrogen protecting groups exemplified in formula (IVA) are benzoyl. If desired, one of the other protecting groups mentioned above may be used in place of the benzoyl group.

When nitrogen is protected by benzoyl, the product from reaction 3 is isolated by chromatography on silica gel to remove residual alkyltin oxides. On the other hand, Jacobus (J. Org. Chem., 44,449 (1979)] can be used to dissolve the crude oil product in methanol and treat this solution with an aqueous solution of potassium fluoride. Precipitating trialkyltin fluoride is removed by filtration and the solvent is evaporated and crystallized from methylene chloride and ethyl ether to give the desired product. In addition, residual tin oxide can be extracted and removed with an aqueous ammonium hydroxide solution.

In reaction 4 of Scheme 1, the compound of formula (IVA) is reacted with a reducing agent to give a compound of formula (VA). Suitable reducing agents include lithium aluminum hydride, beadlide® (solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene), borane in tetrahydrofuran (THF), borane and diiso in dimethylsulfide Butylaluminum hydride (dibal). The solvent must be inert or act as a reducing agent or aid the function of the reducing agent. The optimal solvent will depend on the reducing agent chosen. In general, ethereal solvents (eg THF, ether or dimethoxyethane) are preferred. The reaction can also be carried out in toluene, benzene or hexanes when using Vitride (Vitride trademark) or dibal.

It should be noted that the benzoyl nitrogen protecting group of the compound of formula (IVA) is reduced to the benzyl group in reaction 4, but the latter group continues to function as the nitrogen protecting group. In reaction 5 of Scheme 1, the compound of formula (VA) is reacted with a reactant capable of converting a hydroxyl group to a leaving group of formula (VIA). The above reaction may be carried out in an inert solvent. Preferred solvents will be selected based on the selection of the desired leaving group. In general, suitable solvents include dichloro-ethane, toluene and benzene. On the one hand, the solvent can be used as the halogenating agent.

The reaction temperature is not critical but will generally range from about 70 to about 120 ° C.

In the case of compounds of formula (VIA), the preferred leaving group is chloro. The chloro group may be introduced by reacting the compound of formula (VA) with pure SOCl ₂ at elevated temperature to form a compound of formula (VI) wherein X is chloro. The temperature of this reaction is not critical but will generally range from about 75 ° to 85 ° C.

In reaction 6 in Scheme 1, the ring closure reaction is carried out by reacting a compound of formula (VIA) with a nonnucleophilic base in an inert solvent. If an aqueous base is used, the base should be concentrated to avoid dissolving the water soluble product. Suitable bases include alkaline hydroxides (eg, sodium hydroxide). Suitable solvents include water. Preferred reactants for carrying out the ring closure reaction are 50% aqueous sodium hydroxide. The temperature of reaction 6 is not critical but will generally range from about 15 ° C. to about 35 ° C. When performing ring closure with 50% aqueous sodium hydroxide, the preferred temperature range is about 20 to 25 ° C.

After the cyclization reaction, the protecting group on the nitrogen phase of the compound of general formula (VIIA) is removed by standard techniques to obtain a general compound. Removal of such protecting groups may also be carried out by hydrogenation using Pd (OH) ₂ as catalyst at a temperature of about 55 ° C. to 75 ° C. The pressure is preferably about 3 to 6 atmospheres.

Suitable solvents include alcohols such as C ₁ -C ₄ alcohols. Preferred solvent is methanol. Other suitable hydrogenation catalysts include palladium on carbon.

The pressure of the aforementioned reactions is generally not critical. Except for the above-mentioned hydrogenation reaction, the pressure of the above-mentioned reaction should preferably be in the range of about 0.5 to about 2 atmospheres, more preferably at ambient pressure (ie, about 1 atmosphere).

In reaction 8, the general compound is 1-ethyl-6, 7-difluoro-1, 4-dihydro-4-ox-3-quinoline carboxylic acid, as described in European Patent Publication No. 0215650. Reacted with 7- (1,4-diazabicyclo [3.2.2] non-4-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methane Produces sulfonates (which can be represented by the general formula).

The following examples illustrate the method of the present invention. All melting points related to the examples were not corrected.

[Example 1]

Diethyl-3-amino [N-2-aminoethyl] -1,5-pentanedicarboxylic acid salt

1.89 ml (0.0107 mol) of diethylglutaconate was added dropwise over 5 minutes to 7.15 ml (0.107 mol) of ethylenediamine at room temperature and under nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes and then evaporated in vacuo. 2.6 g (100% yield) of the title product were obtained and used directly in the next step.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 4.1 (4H, q, J = 9 Hz), 3.34 (1H, m), 2.7 (4H, m), 2.47 (4H, d, J = 6 Hz), 1.68 (3H , brs), 1.22 (6H, t, J = 9 Hz).

Example 2

Ethyl-4-benzoyl-5- (2-ethanoic acid) -1, 4-diazepin-7-one

To a 500 ml three necked round bottom flask under nitrogen atmosphere, 8.37 g (0.034 mole) of crude product obtained from Example 1 and 185 ml of dry THF (tetrahydrofuran) were added. To a resulting clear solution cooled to 0 ° C., a solution of 15 g (0.034 mole) of tri-n-butyltintrifluoromethanesulfonate (EJCorey, Tetrahedron Letters, 2419 (1984)) in 50 ml of dry THF. The addition time took 5 minutes and no exothermic reaction was observed The reaction mixture was heated to reflux for 18 hours.

To this solution cooled back to 0 ° C., 9.48 ml (0.068 mole) of triethylamine, 0.34 g (0.068 mole) of N, N-dimethylaminopyridine and 7.93 ml (0.068 mole) of benzoyl chloride were added. Precipitated triethylamine hydrochloride was formed while the reaction was added over 5 minutes. The slurry was stirred for 2.5 hours while warming to room temperature. The mixture was then evaporated to afford a crude residue, which was chromatographed on silica gel [Woelm ™ 32-63 ml] using 10% methanol in ethyl acetate. 8.1 g (78%) of the title compound (melting point: 158-159 DEG C) was obtained.

¹ H NMR (DMSO-360 ° K, 250 MHz) δ: 7.42 (5H, m), (4.851H, br), 4.10 (2H, dq, J = 9Hx), 3.21 (1H, m), 3.05 (4H, s), 2.90 (1HM dd, J = 5 Hz), 2.65 (2H, ddd, J = 15 Hz, J = 7 Hz, J = 6 Hz), 2.45 (1H, dd, J = 15 Hz, J = 6 Hz), 1.15 (3H , t, J = 9 Hz); (IR (CHCl ₃ ) 3410,2960,1730,1670,1440,1200 cm ⁻¹ ; HRMS m / e for C ₁₆ H ₂₀ N ₂ O ₄

Calculation: 304.1423

Found: 304.1386

In a similar manner the following compounds were prepared:

Ethyl-4- [4-bromobenzoyl] -5- (2-ethanoic acid) -1, 4-diazepin-7-one, melting point 158-162 °; Ethyl-4- [1-naphthoyl] -5- (2-ethanolic acid) -1, 4-diazepin-7-one, melting point 145 to 150 ° C; Ethyl-4- [2-naphthoyl] -5- (2-ethanoic acid) -1, 4-diazepin-7-one, melting point 185 to 190 ° C; Ethyl-4- [2-naphthoyl] -5- (2-ethanoic acid) -1, 4-diazepin-7-one, melting point 144 to 145 ° C; And ethyl-4-carbenzyloxy-5- (2-ethanic acid) -1, 4-diazepin-7-one, oil

Example 3

4-phenylmethyl-5- (2-hydroxyethyl) -1, 4-diazepine

To a 1 liter three-neck flask equipped with a magnetic stir bar, cooler, dropping funnel and nitrogen inlet was added 210 ml (0.210 mole) of 1.0 M aluminum hydride in THF solution. Gas was released from the reaction mixture while adding a solution of the above-described compound (8.0 g (0.026 mole)) in 100 ml of THF over 15 minutes at room temperature. When gas evolution stopped (15-20 minutes), the reaction mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and then quenched by the following method: 8 ml of water was added dropwise over 30 minutes to cause a strong exothermic reaction. The resulting slurry was then treated with 8 ml of 15% (w / w) aqueous sodium hydroxide. To this mixture was added 24 ml of water and then the mixture was stirred for an additional 15 minutes, then filtered and the filtrate was concentrated to an oil. 5.65 g (100%) of the title product were obtained. This material is satisfactory for subsequent synthetic uses without purification. However, a small amount of samples were purified by using silica gel chromatography (CHCl ₃ : EtOH: aqueous NH ₄ OH; 9.0: 0.6: 0.4).

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.26 (5H, m), 3.78 (5H, m), 3.28 (1H, M), 2.88 (6H, br m), 2.66 (1H, m), 1.84 (3H , br m), 1.47 (1 H, m); C ¹³ NMR (CDCl ₃ , 75.43 MHz): 138.7, 129.0, 128.4, 127.1, 62.9, 61.9, 52.9, 51.8, 47.1, 46.9, 35.4, 33.8; IR (knit) 3300, 2920, 1735, 1450, 1360, 1240, 1050 cm ^-1 ;

Of HRMS m / e for C ₁₄ H ₂₂ N ₂ O

Calculation: 234.1733

Found: 234.1695

Example 4

4-phenylmethyl-5- (2-chloroethyl) -1, 4-diazepine-dihydrochloride

1.3 g (0.0055 mole) of the product of step 3 above were added to a round bottom flask equipped with a magnetic stirring rod, a cooler and a calcium sulfate drying tube and the system was cooled to 0 ° C. To the oil was added 4.86 ml (0.066 mole) of thionyl chloride. The black reaction mixture was slowly warmed to room temperature and then heated to reflux for 1 hour. The mixture was cooled to room temperature and then quenched carefully with dropwise addition of 30 ml of water. The resulting solution was treated with 3 g of activated carbon and heated to 70 ° C. for 1 hour. This hot solution was filtered through diatomaceous earth (Celite ™) and the filtrate was concentrated to dryness This process was carried out with the aid of a small amount of ethanol (about 10 ml) to help remove traces of final water. The title compound was obtained as foam in 64% yield (1.43 g) This material was used without further purification.

Of HRMS m / e for C ₁₄ H ₂₁ N ₂ Cl

Calculation: 252.1393

Found: 252.1281

Example 5

4-phenylmethyl-1,4-diazabicyclo [3.2.2] nonane

To the 250 ml three-necked round bottom flask in nitrification was added the reaction product of Example 4 (1.43 g, 0.0036 mole) and 12 ml of 50% sodium hydroxide in water. The mixture was stirred for 1 hour and then extracted three times with 50 ml of methylene chloride. The organic layer was washed with brine and then dried over sodium sulfate. Concentration yielded 0.7 g (90%) of the title product. This material was used in the next step without further purification.

¹ H NMR (CDCl ₃ , 250 MHz) δ: 7.30 (5H, m), 3.65 (2H, s), 3.00 (6H, m), 2.89 (1H, m), 2.70 (2H, t, J = 6.2 Hz) , 1.95 (2H, m), 1.6 (2H, m); C ¹³ NMR (CDCl ₃ , 62.9 MHz) 139.67, 128.70, 128.29, 126.91, 61.89, 55.43, 52.70, 51.00, 46.92, 25.61;

Of HRMS m / e for C ₁₄ H ₂₀ N ₂

Calculation: 216.1628

Found: 216.1620

Example 6

1,4-diazabicyclo [3.2.2] nonanditosylate

0.1 g of a palladium hydroxide catalyst (20% on carbon) was added to 0.5 g (0.0023 mole) of methanol solution of the reaction product of Example 5. This mixture was placed under 50 psi hydrogen pressure and heated to 65 ° C. for hydrogenation in a Parr apparatus for a total of 18 hours. At this time, one catalyst was resupplied. The reaction mixture was filtered through Celite ™ and evaporated. The resulting oil (0.222 g) was used without further purification to give 7- (1,4-diazabicyclo [3.2.2] non-4-yl) -1-ethyl-6-fluoro-1, 4- Dihydro-4-oxo-4-quinolinecarboxylic acid methane sulfonate can be prepared. For specific purposes, however, it was dissolved in 2.0 ml of isopropanol and treated with 1.5 g (0.0077 mole) of toluene sulfonic acid in 2.5 ml of isopropanol. A precipitate formed immediately after cooling the slurry to 0 ° C., which was collected. The title compound was obtained in a total yield of 51% (0.6 g).

¹ H NMR (DMSO, 300 MHz) δ: 7.49 (2H, d, J = 9 Hz), 7.11 (2H, d, J = 9 Hz), 3.96 (1H, br.t), 3.54 (4H, m), 3.43 ( 4H, m), 3.31 (2H, m), 2.28 (3H, s), 2.19 (2H, m); C ¹³ NMR (DMSO, 75.43 MHz): 144.7, 138.4, 128.4, 125.5, 50.1, 46.9, 44.8, 37.3, 20.8, 19.8;

Of HRMS m / e for C ₇ H ₁₄ N ₂

Calculation: 126.1158

Found: 126.1158

Claims (2)

Compound of the following general formula.

Wherein Z is CH ₂ and R ² is hydrogen, naphthoyl, substituted naphthoyl, benzyl, substituted benzyl, benzoyl or substituted benzoyl, wherein the substituted naphthoyl, substituted benzyl and substituted benzoyl Each has been substituted with one to three substituents selected from the group consisting of halo, C ₁ -C ₄ alkoxy and C ₁ -C alkyl), W and Q are alkylene crosslinks of the formula —CH ₂ CH ₂ — Form. The compound of claim 1, wherein R ² is benzyl.